CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation

  • Cancer Discov. 2019 Nov;9(11):1538-1555. doi: 10.1158/2159-8290.CD-19-0189.
Reyaz Ur Rasool  1 ,  Ramakrishnan Natesan  1 ,  Qu Deng  1 ,  Shweta Aras  1 ,  Priti Lal  2 ,  Samuel Sander Effron  1 ,  Erick Mitchell-Velasquez  1 ,  Jessica M Posimo  1 ,  Shannon Carskadon  3 ,  Sylvan C Baca  4 ,  Mark M Pomerantz  4 ,  Javed Siddiqui  5 ,  Lauren E Schwartz  2 ,  Daniel J Lee  6 ,  Nallasivam Palanisamy  3 ,  Goutham Narla  7 ,  Robert B Den  8 ,  Matthew L Freedman  4 ,  Donita C Brady  1  9 ,  Irfan A Asangani  10  9  11
Affiliations
  • 1. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2. Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 3. Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 5. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • 6. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 7. Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • 8. Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 9. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 10. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. [email protected].
  • 11. Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
PMID: 31466944 DOI: 10.1158/2159-8290.CD-19-0189
Abstract

Metastatic castration-resistant prostate Cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by Androgen Receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. In vivo, THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC.See related commentary by Russo et al., p. 1490.This article is highlighted in the In This Issue feature, p. 1469.

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